_ROVIDED. Inadequate bone cell-surface interactions associated with existing synthetic materials have hindered the development of biologically active osseous implants. The objective of this application is to engineer advanced bioadhesive materials presenting fibronectin (FN)- and collagen (COL-I)-mimetic motifs that direct osteoblast function to promote bone formation and osseointegration. Our central hypothesis is that controlled presentation ot mixed integrin-specific ligands will direct cell adhesion and signaling to upregulate osteoblast differentiation and matrix mineralization thereby enhancing bone repair. The rationale for this work is that it will establish a robust biomolecular approach to overcome inadequate cell-material interactions associated with current synthetic materials. Aim 1: Identify surface formulations of mixed FN- and COL-I-mimetic ligands that promote osteoblastic differentiation and matrix mineralization. We hypothesize that controlled presentation of mixed integrin-specific ligands will direct osteogenic cell adhesion, osteoblast-specific gene expression, and nineralization compared to single ligand and non-functionalized surfaces. These surface formulations will then be ased to engineer biomimetic implant coatings. Aim 2: Evaluate the ability of integrin-specific biomimetic surfaces :o promote osseointegration. It is hypothesized that titanium implants functionalized with non-fouling polymer brushes that present mixed FN- and COL-I-mimetic ligands will exhibit enhanced bone apposition and pull-out strength compared to single ligand-functionalized and unmodified implants. This work is fundamentally different from current biomimetic approaches using short adhesive peptides (e.g. RGD) in that it concentrates on engineering integrin specificity. This is a key consideration because different integrin receptors activate different signaling pathways and gene expression programs. This research is expected to yield the following outcomes: (1) valuate the extent to which presentation of multiple integrin-binding ligands enhances osteoblastic differentiation !and mineralization, and (2) establish the potential of this biomolecular approach as a robust surface treatment for osseous implants. Collectively, these studies will validate this biomolecular surface engineering approach for developing biologically active implants for enhanced bone repair. _ERFORMANCE SITE(S) (organization, city, state) Georgia Institute of Technology, Atlanta, GA KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Garcia, Andr6s J. Georgia Inst. Technology Collard, David M. Georgia Inst. Technology Reyes, Catherine D. Georgia Inst. Technology Schwartz, Zvi Hebrew Univ./Georgia Inst. Technol. TBA Georgia Inst. Technology TBA Georgia Inst. Technology TBA Georgia Inst. Technology in the format shown below. Role on Project Principal investigator Co-principal investigator Graduate student Consultant Postdoctoral fellow Postdoctoral fellow Graduate student Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] No PHS 398 (Rev. 05/01 ) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. PrincipInavlestigator/PDriorecgtora(mLast, First, Middle): Garcia, Andres Jose The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbe_ Face Page .................................................................................................................................................. 1 Description,